Budesonide-Formoterol Metered-Dose Inhaler vs Fluticasone-Salmeterol Dry-Powder Inhaler

Abstract

Importance: Transitioning from metered-dose inhalers to propellant-free dry-powder inhalers could reduce health care-related greenhouse gas emissions, but the clinical difference in outcomes that may be associated with this switch is uncertain.

Objective: To evaluate the clinical difference in outcomes associated with a July 2021 Veterans Health Administration (VHA) formulary change that replaced budesonide-formoterol metered-dose inhaler with fluticasone-salmeterol dry-powder inhaler for the treatment of chronic obstructive pulmonary disease and asthma.

Design, setting, and participants: This within-person, self-controlled case series (SCCS) and matched observational cohort study (cohort study) used data from the US Veterans Affairs health care system from January 2018 through December 2022. Veterans who were prescribed a combination inhaler before and after the formulary change were included in both the SCCS and cohort study. Data were analyzed between April 19, 2024, and April 4, 2025.

Exposures: Treatment with budesonide-formoterol metered-dose inhaler vs fluticasone-salmeterol dry-powder inhaler.

Main outcomes and measures: Rescue medication use (albuterol and prednisone fills), emergency department visits, and hospitalizations (all-cause, respiratory-related, and pneumonia-specific) were assessed.

Results: Following the VHA formulary change, 260 268 patients switched from budesonide-formoterol metered-dose therapy to fluticasone-salmeterol dry-powder therapy. In the SCCS (median [IQR] age, 71 [62-75] years; 91% male), among patients who switched inhalers and experienced the adverse outcomes of interest, treatment with fluticasone-salmeterol dry-powder inhaler therapy was associated with a 10% decrease in albuterol fills (incidence rate ratio [IRR], 0.90 [95% CI, 0.90-0.91]), a 2% increase in prednisone fills (IRR, 1.02 [95% CI, 1.01-1.03]), a 5% increase in all-cause emergency department visits (IRR, 1.05 [95% CI, 1.04-1.06]), an 8% increase in all-cause hospitalizations (IRR, 1.08 [95% CI, 1.06-1.09]), a 10% increase in respiratory-related hospitalizations (IRR, 1.10 [95% CI, 1.07-1.14]), and a 24% increase in pneumonia-specific hospitalizations (IRR, 1.24 [95% CI, 1.17-1.31]). In the cohort study of 258 557 patients (mean [SD] age, 68.9 [11.3] years; 94% male), those who switched to a fluticasone-salmeterol dry-powder inhaler had no difference in mortality (1.89% vs 1.90%; adjusted absolute difference, -0.01 percentage points [95% CI, -0.12 to 0.10 percentage points]) but had increases in all-cause hospitalizations (16.14% vs 15.64%; adjusted absolute difference, 0.49 percentage points [95% CI, 0.21-0.78 percentage points]), respiratory-related hospitalizations (3.15% vs 2.74%; adjusted absolute difference, 0.41 percentage points [95% CI, 0.27-0.55 percentage points]), and pneumonia-related hospitalizations (1.15% vs 1.03%; adjusted absolute difference, 0.12 percentage points [95% CI, 0.04-0.21 percentage points]) at 180 days after the switch compared with matched patients who did not switch.

Conclusions and relevance: The study found that the VHA formulary transition from budesonide-formoterol metered-dose inhaler to fluticasone-salmeterol dry-powder inhaler was associated with increased health care utilization, suggesting potential harm and the need to reevaluate this policy change.

Figure 1.. Schematic of the Self-Controlled Case Series Study Design

The figure shows the timeline of exposures, outcomes, and time-varying covariates for a hypothetical patient who switches from budesonide-formoterol metered-dose inhaler (MDI) therapy to fluticasone-salmeterol dry-powder inhaler (DPI) therapy following the national formulary change. The patient is aged 65 to 70 years during the course of the study period and splits time between Michigan (census division 3 [div 3]) and Florida (census division 5 [div 5]). Using the self-controlled case-series method, outcome rates are compared across exposure periods, adjusting for the time-varying covariates of age, study quarter, and geographic region. eFigure 4 in Supplement 1 demonstrates how this hypothetical patient timeline is represented in the study dataset. ED indicates emergency department.

Figure 2.. Inhaler Dispensing Before and After the National Formulary Change in the Self-Controlled Case Series Cohort

The figure shows the number of monthly controller inhalers dispensed (budesonide-formoterol metered-dose inhaler [MDI], fluticasone-salmeterol dry-powder inhaler [DPI]) or other combination inhaled corticosteroid, long-acting β-agonist, or long-acting muscarinic antagonist from January 1, 2018, to December 31, 2022, among 347 486 patients who received controller inhalers during the study period both before and after the formulary switch. The increasing number of budesonide-formoterol MDIs over time reflects the larger number of patients included in the cohort leading up to the formulary change. There were 272 538 patients prescribed controller inhalers prior to the formulary switch who were excluded from the study cohort because they were not dispensed a controller inhaler after the formulary switch. The vertical dashed lines indicate the formulary change period from July 1, 2021, to September 30, 2021.

Figure 3.. Clinical Outcomes Among Patients Who Switched Inhalers in the Self-Controlled Case Series Cohort

The figure shows the relative incidence of adverse health outcomes during periods of fluticasone-salmeterol dry-powder inhaler (DPI) use vs periods of budesonide-formoterol metered-dose inhaler (MDI) use among those who experienced the outcomes of interest. In this analysis, we allowed a 33% grace period for inhaler fills to define exposure periods. IRR indicates incidence rate ratio. ^aAlbuterol represented as inhaler-equivalent medication fills. ^bPrednisone represented as discrete courses of the medication filled. ^cRespiratory cause defined as a principal diagnosis code of chronic obstructive pulmonary disease or asthma.